Associate Professor in the Department of Epidemiology
Associate Professor in Medicine, Harvard Medical School
My research seeks to elucidate mechanisms of cancer causation using a molecular epidemiology approach. This approach combines epidemiology and molecular biology techniques to identify and subsequently characterize biological markers which can then be used in the study of carcinogenic mechanisms and in the early detection and prevention of neoplasia. Using biological samples and over 35 years of questionnaire data on lifestyle, medical history, and diet from the longstanding Harvard Cohorts, Nurses’ Health Study 1, 2 and Health Professional Follow-up Study, I have identified genetic variants that modify an individual’s risk of cancer. My research has scientific impact as evidenced by over 160 publications many of which have been highly cited, and by continued funding from the NIH, the American Cancer Society and other agencies as an independent investigator. My administrative responsibilities include directing the Dana Farber Cancer Institute/Harvard Cancer Center High Throughput Genotyping core facility. This core serves genotyping and sequencing needs of the Harvard community as well as national and international researchers. The remainder of my time is spent teaching and mentoring students, postdoctoral fellows and junior faculty in the area of cancer research and genetic susceptibility. A question that drives my lab’s research: how does the environment interact with genetic variants to influence susceptibility to hormonal cancers? Examples include mechanistic analysis of genetic variants and telomere length measurements.
Endometrial cancer risk factors and mechanisms
I chose to focus on endometrial cancer (EC) as very little was known in terms of genetic susceptibility and this disease has well defined exposures, suggesting it could serve as a platform for developing models of other hormonally sensitive cancers, including breast and ovarian cancer. I’m recognized for developing a unique approach combining molecular biology and epidemiology to understand cancers.
I have shown that genetic variants can predispose a woman to endometrial cancer and that her genetic risk can be modified by lifestyle exposures, like adiposity. This work has led to a number of highly cited papers in the field. In the PNAS study (De Vivo et al. 2002), we discovered novel variants in the progesterone receptor gene (PR), functionally characterized the variants, and showed association with EC risk and effect modification by adiposity. In 2002, this work was held as a standard in the field molecular epidemiology studies. My group extended these findings to breast cancer and ovarian cancer. Interestingly, the molecular mechanism by which the PR variant increased breast cancer risk was similar (Huggins et al 2005). Mechanistic studies on ovarian cancer are ongoing. The PR variant has been investigated by several groups in relation to breast and ovarian cancer and other conditions such as endometriosis and infertility leading to large number of papers.
Because of my reputation in the field of endometrial carcinogenesis, I led the NCI-sponsored international endometrial cancer consortium (E2C2) of 12 national and international studies to conduct genome-wide association studies of EC. I received NIH funding (ARRA grant 4.2 million for 2 years) that resulted in the identification of additional risk genetic loci (De Vivo et al, 2013). My current research focuses on EC tumor tissue molecular subtyping and estimating associations between risk factors and somatic alterations. Work resulting from this research will define tumor sub classifications and refine risk estimates in what is now considered a relatively homogenous disease. By focusing on different aspects of EC, I seek improved understanding of the basic mechanisms involved in endometrial carcinogenesis. Such findings would improve endometrial cancer risk assessment allowing for more targeted and cost-effective intervention strategies for women at high risk.
Telomeres and disease risk
Another important theme of my lab’s research is the relationship between the length telomeres, repeats at the end of chromosomes, and susceptibility to disease, especially cancer. Telomere length (TL) and telomerase play central roles in carcinogenesis and have both genetic and environmental determinants. In 2007, a new quantitative PCR (Q-PCR) method to measure telomere length was developed that made it possible to study health effects of telomere length in large human populations. Using the Q-PCR method we can now measure telomere lengths in peripheral blood lymphocytes as a proxy for accelerated aging and onset of chronic diseases, including cancer. The tremendous potential of using this assay to expand the role of telomere length in cancer etiology and lifestyle factors was something that became clear to me. In addition, we were well positioned with our large prospective studies to challenge the conventional wisdom that short TL may portend poor health outcomes, including cancer incidence. Many of epidemiological findings on TL and cancer risk were based on retrospective studies and/or small studies which have limitations. Participants in most of these studies had already been subjected to chemotherapy, irradiation, or both, which may have impacted hematopoiesis and consequently shortened TL. Furthermore, sample sizes were often too small which limited the ability to derive valid conclusions. However, we have shown that mechanisms that link TL with human health and disease are much more complex than this oversimplified view. Findings from our studies reveal that long telomeres are predictive of incidence some cancers including melanoma, and prostate, and short telomeres are associated with higher incidence of bladder, a smoking-related cancer, mortality and cancer survival.
Telomeres shorten over time in somatic cells as a result of cell proliferation. A hypothesis in the field suggests that in addition to “normal” shortening, inflammation and oxidative stress cause further shortening of telomeres. My group set out to test this hypothesis, given that certain exposures, including smoking and obesity, can cause disease through these mechanisms. In addition, short telomeres are associated with chronic stress, and can differ by gender and ethnicity, whereas physical activity or adherence to Mediterranean diet can delay telomere shortening (BMJ, covered by numerous news outlets and magazines) . Our GWAS of telomere length confirmed that variants at the TERC, which encodes the protein component of telomerase enzyme, locus are predictive of length. Surprisingly, we observed a positive correlation between paternal age at birth and offspring telomere length that may result in inheriting longer telomere lengths from older fathers, indicating that children of older fathers may inherit longer telomeres, potentially impacting health.
We have shown that telomere length is unlike most other genetic features in that it can be impacted by environment factors both positively (physical activity, meditation, diet) and negatively (obesity, smoking, stress). In collaboration with NCI, we have shown that TL may also have clinical implications. Our study provides evidence of a survival benefit associated with longer donor LTL in patients transplanted for Severe Aplastic Anemia (JAMA). I continue to build on these findings and oversee several analyses to understand how lifestyles impact TL and chronic disease.
My reputation in the EC and telomere biology communities has led to invitations to serve on several grant study sections and to give national and international talks, seminars and workshops. Recently I was awarded an R13 to organize a two day international symposium, held at Harvard School of Public Health (March, 2014), to develop priorities for future research that will identify the programs that will have the greatest impact on reducing risk and improving survival from endometrial cancer. Advances in Endometrial Cancer Epidemiology and Biology Symposium, brought together experts from the fields of epidemiology, biology, pathology, psychology, health policy, and clinical practice to exchange knowledge and ideas. This symposium was very highly praised in the official NCI evaluation and recommended to be hosted again in two years. My recent publication in BMJ regarding adherence to a mediterranean diet and longer telomere lengths stirred an enormous amount of interest in the role of telomeres and overall health (covered by numerous national and international news outlets, The Altmetric Score is 580, “Article is amongst the highest ever scored in BMJ journal (ranked #32 of 21,210)”: 22 news outlets, 9 blogs, 437 tweets, 98 facebook pages (http://www.altmetric.com/details.php?domain=www.bmj.com&citation_id=2944015).
I am active in teaching and mentoring at HSPH, including as the primary instructor for Epi 249: Molecular Biology for Epidemiologists. This course has been given a rating of “outstanding” consistently since I started teaching it 2000 and I was presented with a teaching Citation, in appreciation of my excellence in teaching. I have mentored many students including over 7 doctoral, 7masters, 7 postdoctoral fellows, served on over 2 dozen thesis committees and medical professionals (Costenbader, MD, Kabhrel, MD, Okereke, MD) all of whom received an R01 under my mentorship.
I have over 20 years of experience studying the etiology of chronic diseases, specifically cancer, in women, and I am considered a world leader in the field of genetic epidemiology. I am well known for my work in analyzing inherited susceptibility to cancer using molecular techniques and studying molecular markers of environmental exposures. My lab is considered the leading lab for using the Q-PCR protocol to measure telomere lengths. I have trained scientists from Germany, Spain and Belgium as well numerous scientists from the United States on telomeres.
B.S., M.P.H., Ph.D.